Project Summary (Abstract) The overall goal of the proposed study is to delineate consequences and determinants of adolescent marijuana (MJ) consumption using the co-twin control approach. MJ is the most commonly used illicit drug with a typical onset of use in adolescence, a period of continued brain development and increased vulnerability to detrimental effects of drugs of abuse. Previous studies have established associations between chronic and/or early MJ exposure and alterations in brain function, behavior, and cognition, including deficits in self-regulation of behavior and increased impulsivity that may increase the risk for transition to the use of ?harder? drugs, as well as neurocognitive dysfunctions that resemble those seen in schizophrenia. However, most existing studies relied on case-control, correlational designs precluding strong causal inferences. It remains unclear whether deficits found in MJ users represent the consequences of MJ use or, conversely, pre- existing factors of risk for MJ use. This unresolved issue represents a critical gap in knowledge that hinders the development of prevention, intervention, and treatment methods, as well as evidence-based MJ related public policy. The proposed study seeks to address this gap in knowledge through the implementation of the powerful co-twin control design. In monozygotic twin pairs discordant for MJ use history, twins have the same degree of genetic liability and share many critical aspects of environment but differ with respect to MJ exposure. Thus, the non-exposed twins represent ideal controls for their MJ-exposed co-twins. The co-twin control method is thus a cost- and time-efficient approach that can be viewed as complimentary to longitudinal studies that require very large samples to ensure sufficient representation of high-exposure cases and long time (about 10 years) to achieve conclusive results. The proposed study will use a set of theory-driven experimental paradigms to collect neurophysiological, behavioral, and cognitive measures that tap into specific neurocognitive component processes that have been linked to (i) impulsivity and addiction risk (response inhibition, error monitoring, and selective attention) and/or (ii) increased risk for schizophrenia (sensory and sensorimotor gating, auditory deviance detection). These measures will be assessed in 280 adolescent and young adult twins with and without MJ use history aged 19-36. The twins will be drawn from existing epidemiological studies of the PI and co-investigators and selected, based on existing data, to ensure sufficient variability in the age of onset, extent of exposure, length of abstinence, and twin pair concordance versus discordance for MJ use. Specific aims will be: 1) To examine associations between MJ use and neurocognitive functioning in adolescents and young adults and to determine the extent to which these associations depend on severity of exposure, age of onset of MJ use, and length of abstinence and 2) To isolate, using co-twin control approach, consequences of MJ use from pre-existing alterations in brain function and cognition.